The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

Abstract

Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.

Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer

“…Several difficulties exist with this type of application, such as degradation of nucleases by biological systems, poor permeability to cell membranes, the need to increase the binding force for complementary sequences, optimization of the delivery method to target tissue, and the occurrence of off-target and unwanted toxicities [103]. Over time, a number of solutions have been developed, including the use of different chemical modifications (phosphodiester linkages, ribose backbone, 2 -O-(2-methoxyethyl), 2 -O-methyl, 2 -locked nucleic acid, and 2 -fluoro) to improve stability and different delivery vehicles to improve transportation (liposomes, polymers, and viruses) [104].…”

A novel method for producing functionalized vesicles that efficiently deliver oligonucleotides in vitro in cancer cells and in vivo in mice

“…Most oligonucleotide drugs have sequences that complement their DNA or RNA targets [28]. Oligonucleotide drugs include small interfering RNAs (siRNA) [30,31], antisense oligonucleotides (ASOs) [32,33] and microRNAs (miRNAs) [34]. Some of the challenges of oligonucleotide drugs are inducing an immunogenic response, enzymatic degradation, and off-target effects [27].…”

“…ASOs are short 15-25 base pair polynucleotides that can be designed to bind to disease-related targets [32,33]. Mechanistically, they bind to a target RNA, which induces RNA degradation [33].…”

“…ASOs are short 15-25 base pair polynucleotides that can be designed to bind to disease-related targets [32,33]. Mechanistically, they bind to a target RNA, which induces RNA degradation [33]. They also cause steric hindrance by chemically modified ASOs inhibiting RNA degradation [33].…”

Oligonucleotides-Based Therapeutics

“…Rapid progress in nucleic acid chemistry gave rise to many ASO analogs with improved pharmacological properties, including increased resistance to nucleases degradation, enhanced binding to the RNA target, improved bioavailability, or reduced toxicity. Mechanisms of action and chemical modifications of ASOs have been comprehensively reviewed by Gagliardi and Ashisawa [4] in this issue.…”